The extreme heterogeneity of human cancers, due to a wide variety of genetic alterations and microenvironmental stresses, presents significant challenges for effective treatments. Robust aerobic glycolysis and significant perfusion defects cause an accumulation of lactic acid, termed lactic acidosis, in many solid human tumors. Evidence is accumulating for an active role of lactic acidosis in affecting tumor phenotypes, treatment responses and clinical outcomes. While lactic acidosis inhibits tumor growth and glycolysis, cancer cells that survive exposure to lactic acidosis for an extended period of time often metastasize and resist radio- and chemotherapeutics. Therefore, specifically targeting cancer cells under lactic acidosis will help reduce treatment resistance and improve clinical outcomes. Although significant efforts have been mead to target cells under hypoxia, relatively little attention has been paid to targeting cells under lactic acidosis. To fill this gap, we propoe a systematic approach to discover strategies to specifically target cells under lactic acidosis by applying the concept of """"""""synthetic lethality"""""""" - genes whose disruptions, while normally tolerated, confer lethality under lactic acidosis. First, we will integrate metabolomic and transcriptional profiling of human cancer cells to identify the metabolic inflexibilities and bioenergetic restrictions imposed by lactic acidosis. Second, we will perform genome- wide, synthetic lethal RNAi screens to identify genes which are essential for survival only under lactic acidosis. Then through both genetic and chemical inhibition, we will evaluate strategies for targeting the identified pathways and genes that are critical for cells under lactic acidosis. In addition, we wil test whether the DNA amplification of the contextually- essential genes confers any survival advantage under lactic acidosis and renders cells uniquely susceptible to their targeting. This proposal presents an innovative and integrative approach to identify novel strategies to eradicate cancer cells under lactic acidosis to achieve a tangible and positive impact on patients'outcomes.
Cancer is an important public health risk. Since lactic acidosis is a prominent feature in most solid tumors, our proposal on the identification of novel strategies to target cells under lactic acidosis can improve the treatment outcomes and improve the health of patients who suffer from solid tumors.
|Tang, Xiaohu; Wu, Jianli; Ding, Chien-Kuang et al. (2016) Cystine Deprivation Triggers Programmed Necrosis in VHL-Deficient Renal Cell Carcinomas. Cancer Res 76:1892-903|
|Tang, X; Ding, C-K; Wu, J et al. (2016) Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling. Oncogene :|
|Syu, Jhih-Pu; Chi, Jen-Tsan; Kung, Hsiu-Ni (2016) Nrf2 is the key to chemotherapy resistance in MCF7 breast cancer cells under hypoxia. Oncotarget 7:14659-72|
|Horton, Janet K; Siamakpour-Reihani, Sharareh; Lee, Chen-Ting et al. (2015) FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target. Radiat Res 184:456-69|
|Keenan, Melissa M; Liu, Beiyu; Tang, Xiaohu et al. (2015) ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via Î±-ketoglutarate. PLoS Genet 11:e1005599|
|Jiang, Xiaolei; Nevins, Joseph Roy; Shats, Igor et al. (2015) E2F1-Mediated Induction of NFYB Attenuates Apoptosis via Joint Regulation of a Pro-Survival Transcriptional Program. PLoS One 10:e0127951|
|Mo, Lihong; Bachelder, Robin E; Kennedy, Margaret et al. (2015) Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78. Mol Cancer Ther 14:747-56|
|Bhattacharyya, Jayanta; Bellucci, Joseph J; Weitzhandler, Isaac et al. (2015) A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models. Nat Commun 6:7939|
|Tang, Xiaohu; Keenan, Melissa M; Wu, Jianli et al. (2015) Comprehensive profiling of amino acid response uncovers unique methionine-deprived response dependent on intact creatine biosynthesis. PLoS Genet 11:e1005158|
|Keenan, Melissa M; Chi, Jen-Tsan (2015) Alternative fuels for cancer cells. Cancer J 21:49-55|
Showing the most recent 10 out of 41 publications